Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase
Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase
复制标题
DOI：
10.1371/journal.pone.0065235
复制
发表时间：
2013-06-12
期刊：
影响因子：
3.7
通讯作者：
Brady, Scott T.
中科院分区：
文献类型：
--
作者：
Morfini, Gerardo A.;Bosco, Daryl A.;Brady, Scott T.
运动神经元轴突的死亡退化是与超氧化物歧化酶 1 (SOD1) 突变相关的家族性肌萎缩侧索硬化症 (FALS) 的一个既定特征，但致病性 SOD1 的轴突自主效应仍不清楚。 FALS 中受影响的运动神经元的特征包括异常激酶激活、异常神经丝磷酸化和快速轴突转运 (FAT) 缺陷，但这些致病事件之间的功能关系尚不清楚。在分离的鱿鱼轴浆中进行的实验表明，FALS 相关的 SOD1 突变多肽通过涉及 p38 丝裂原激活蛋白激酶途径的机制抑制 FAT。突变体 SOD1 激活小鼠脊髓、神经母细胞瘤细胞和鱿鱼轴浆中的神经元 p38。活性 p38 MAP 激酶磷酸化 kinesin-1，并且该磷酸化事件抑制 kinesin-1。最后，囊泡运动测定揭示了 p38 对 FAT 的先前未被认识的异构体特异性影响。 p38 通路的轴突自主激活代表了 FALS 连接的 SOD1 蛋白毒性功能的新获得，与 ALS 神经退行性变特征的死亡模式一致。
Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.